Metabolic syndrome (MetS) is a growing problem around the globe. According to most definitions, this syndrome is characterized by the concurrent manifestation of 3 or more of the following five factors: enlarged waist circumference (WC), elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL), high blood pressure and impaired glucose tolerance. Diagnostic criteria for this syndrome have been defined by several entities and the definition has changed with time (1). One criterion that remains a subject of debate is WC. Measuring WC is a non-invasive technique to assess abdominal obesity. Ethnicity dependent cutoffs for WC have been established, however those designated for the Mexican population have been shown to be inadequate for accurately assessing risk for disease because they are based on a South Asian population (2, 3).
MetS and obesity itself are the product of a complex interplay between environment, lifestyle, diet and genetics. These factors can interact with each other, making developing interventions and determining causal relationships difficult. Investigations into the interactions between diet and our genetic code have wielded promising data suggesting that changing the diet can affect how our genes are expressed (4). Research is targeting specific nutrients both on the macro and micro scales. Vitamin A and carotenoids are one such target.
Retinoids are key in facilitating many physiological functions from cell differentiation and embryogenesis to vision and lipid metabolism (5). Vitamin A and carotenoids are compounds that demonstrate the activity of retinoids and have shown importance in determining health outcomes related to obesity and dyslipidemia. The availability of retinoids for body processes is somewhat dependent on the activity of β, β-carotene-15,15-oxyegenase 1 (BCO1). However, studies show that humans exhibit both low and high conversion rates of provitamin A carotenoids to functional retinoids. This may be due to single nucleotide polymorphism (SNPs) within and upstream of the BCO1 locus impart changes in the efficiency of conversion of β-carotene to retinol (6, 7). Given the connection between carotenoid derivatives and lipid metabolism it is interesting that the association between the genotype of BCO1 and the lipid profile has been poorly examined in humans.
The work presented here is based on research from the Universities of San Luis Potosi and Illinois: A Multidisciplinary Investigation on Obesity, Genetics and Socio-environment (UP AMIGOS) project. A large cohort of college applicants to the University of San Luis Potosi participated in this cross-sectional study. Biological, anthropometric, dietary, physical activity, and psychological data was collected from close to 10,000 individuals. The objectives of this research are as follows: 1) Examine the prevalence of MetS in a cohort of young Mexican adults based on three sets of diagnostic criteria in order to determine if a proposed set of WC cutoffs correlate more positively with components of metabolic syndrome, 2) Investigate the association between BCMO1 SNPs and serum lipid levels in college-age individuals from the UPAMIGOS cohort and further, to ascertain whether dietary intake of carotenoids has an effect on these relationships, and 3) Conduct a pilot study, implementing a protocol developed for the collection and measurement of serum carotenoids in addition to dietary intake.
The overall hypothesis of this work is that a cohort of young Mexican adults will show evidence of risk for factors of MetS. The lipid profile in this population will be associated with genetic variation in the BCO1 locus. Dietary intake of these individuals will be a mediating factor in this relationship.
The first study presented here examines the prevalence of MetS in a subset of participants from the UP AMIGOS project (n=668) aged 18 to 25 years. These individuals provided anthropometric and biological data as well as blood for measurement of serum lipids. MetS and components thereof were diagnosed according to the criteria used International Diabetes Federation (IDF), American Heart Association (AHA) and a proposed set based on a sample of Mexicans (MEX). The only difference among these three are the WC cutoffs which were defined for men and women as follows: 90 and 80 cm by IDF, 102 cm and 88 cm by AHA and 98 cm and 84 cm by MEX. The prevalence of MetS in this cohort of young Mexican adults was less than 15% across all definitions. Correlations between WC and body mass index (BMI) and other components of MetS (TG, HDL, blood pressure, and elevated fasting blood glucose) were examined. The MEX WC cutoffs were found to be more highly positively correlated with diastolic blood pressure and negatively correlated with HDL in females than the other sets of WC cutoffs. Additionally, average TG and diastolic blood pressure was higher in males that had elevated WC according to the MEX criteria than those identified by the IDF and AHA cutoffs. Our study shows that the current WC cutoff criteria used to assess risk may not be adequate for identifying individuals who are truly at risk. WC criteria that are specific and sensitive enough to detect those in the Mexican population who are truly at risk will help public health entities allocate scarce resources more effectively.
In the second study, 767 individuals, aged 18 to 25 years, who had the most complete data and provided blood and serum for analysis were included. DNA was extracted from whole blood and genotypes for five SNPs within and upstream of the BCO1 gene locus were determined. Also, 511 of these participants took the time to adequately fill out a food frequency questionnaire for assessment of dietary intake. Significant associations were found between the minor alleles of BCO1 SNPs rs6564851 and rs6420424 and increased total cholesterol (TC), low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) levels. These associations were not only maintained, but became stronger in a subset of this sample (n=511) when we accounted for dietary fat and carotenoid intake. Our analyses for objective two reveal that SNPs in BCMO1 were associated with plasma lipid levels and that is relationship is mediated by dietary intake. Knowing the risk for abnormal lipid levels is increased depending on genotype for this enzyme could be a target of potential interventions in the future that address both dietary and genetic interactions.
In addition, we recruited a small pilot cohort (n=20) to assess the feasibility of collecting blood and serum samples for the measurement of carotenoids in this population. The implementation of the pilot study was successful. Our study sample showed few differences from the larger UP AMIGOS cohort which indicated that this protocol can be successfully replicated in the larger cohort. Positive correlations were observed between the measured intake of retinol and lycopene with estimated intakes of α-carotene, lycopene and its isoforms. Also, circulating levels of carotenoids were significantly correlated with the lipid profile of study participants. The successful execution of this unique data collection protocol has proven feasible with the available staff and facilities available to our collaborators. The relationships between intake and plasma levels of carotenoids show that assessment of intake of these nutrients is possible using a FFQ and that this could aid in the development of a tool that can be used to assess carotenoid status and, subsequently, health in this population.
Looking toward the future we would expand our analysis to produce WC cutoffs for this specific population. Examining the correlation of a specific set of WC criteria with components of MetS would allow us to validate these cutoffs as accurate assessment criteria. As the longitudinal arm of the UP AMIGOS project continues we hope to investigate the details of the relationship between genotype of BCO1 and the lipid profile. Future intervention studies would be aimed at examining the effect of carotenoid administration on the lipid profile based on low and high converter genotypes. Overall, this work will contribute to the improvement of our ability to assess risk for metabolic disease in this population.
References
1. Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the Metabolic Syndrome: A joint interim statement of the International Diabetes Federation task force on epidemiology and prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-5.
2. The IDF consensus worldwide definition of the metabolic syndrome. 2005. https://www.idf.org/webdata/docs/MetS_def_update2006.pdf.
3. Alonso AL, Munguía-Miranda C, Ramos-Ponce D, Hernandez-Saavedra D, Kumate J, Cruz M. Waist perimeter cutoff points and prediction of metabolic syndrome risk. A study in a Mexican population. Arch Med Res. 2008;39(3):346-51.
4. Jenab M, Slimani N, Bictash M, Ferrari P, Bingham SA. Biomarkers in nutritional epidemiology: applications, needs and new horizons. Hum Genet. 2009;125(5-6):507-25.
5. Gudas LJ. Emerging roles for retinoids in regeneration and differentiation in normal and disease states. BBA - Mol Cell Biol Lipids. 2012;1821(1):213-21.
6. Lietz G, Oxley A, Leung W, Hesketh J. Single nucleotide polymorphisms upstream from the beta-carotene 15,15'-monoxygenase gene influence provitamin A conversion efficiency in female volunteers. J Nutr. 2012;142(1):161s-5s.
7. Hendrickson SJ, Hazra A, Chen C, Eliassen AH, Kraft P, Rosner BA, et al. beta-Carotene 15,15'-monooxygenase 1 single nucleotide polymorphisms in relation to plasma carotenoid and retinol concentrations in women of European descent. Am J Clin Nutr. 2012;96(6):1379-89.